CHARACTERIZATION OF BIBN-99 - A LIPOPHILIC AND SELECTIVE MUSCARINIC M(2)-RECEPTOR ANTAGONIST

The present study was designed to characterize the receptor selectivit y profile of the novel muscarinic M2 receptor antagonist BIBN 99 ]acet yl]-6H-pyrido[2,3-][1,4]benzodiazepin-6-one). In radioligand binding s tudies BIBN 99 showed high affinity for m2/M2 sites (pK(i) = 7.52/7.57 ), intermediate affinity for m4 sites (pK(i) = 6.76) and low affinity for ml/M1 (pK(i) = 5.97/6.17), m3/M3 (pK(i) = 6.11/6.04) and m5 sites (pK(i) = 5.84). Functional studies in vitro showed BIBN 99 to be a com petitive antagonist and to have an 11- to 25-fold higher affinity for M2 receptors than for putative M1 receptors in the rabbit vas deferens or M3 receptors in guinea-pig trachea. In vivo studies revealed that BIBN 99 is able to cross the blood-brain barrier, and although showing an approximately 3-fold higher affinity for M2 binding sites BIBN 99 appeared to be 7- to 18-fold less potent than AF-DX 116 in inhibiting muscarinic agonist or vagally induced bradycardia in rats and guinea-p igs. The results show that BIBN 99 is the first lipophilic muscarinic M2 receptor antagonist to have remarkable M2 versus M1 selectivity (30 -fold). In addition, BIBN 99 possesses central nervous system activity and only minor peripheral cardiac effects.